| Characteristic | Overall N = 1801 |
ABC N = 301 |
ACB N = 301 |
BAC N = 301 |
BCA N = 301 |
CAB N = 301 |
CBA N = 301 |
p-value2 |
|---|---|---|---|---|---|---|---|---|
| Age (years) | 32 (8) [18, 45] | 33 (8) [19, 44] | 31 (7) [18, 42] | 31 (7) [20, 44] | 33 (8) [19, 45] | 32 (7) [21, 44] | 31 (7) [20, 44] | 0.6 |
| Race | 0.9 | |||||||
| Â Â Â Â Black | 64 (36%) | 12 (40%) | 13 (43%) | 12 (40%) | 10 (33%) | 8 (27%) | 9 (30%) | |
| Â Â Â Â White | 52 (29%) | 8 (27%) | 9 (30%) | 7 (23%) | 7 (23%) | 12 (40%) | 9 (30%) | |
| Â Â Â Â Other | 64 (36%) | 10 (33%) | 8 (27%) | 11 (37%) | 13 (43%) | 10 (33%) | 12 (40%) | |
| Female | 81 (45%) | 13 (43%) | 11 (37%) | 16 (53%) | 14 (47%) | 12 (40%) | 15 (50%) | 0.8 |
| 1 Mean (SD) [Min, Max]; n (%) | ||||||||
| 2 Kruskal-Wallis rank sum test; Pearson’s Chi-squared test | ||||||||
preliminary assessment and comparison of systemic and local Pharmacokinetics (PK) of Pill A, Gel B, and Gel C and the correlation of PK with adherence measures and the occurrence of adverse events
Blood PK
\[ Y_{ik} = \mu + b_{k} + \pi_i + \tau_{i} + \lambda_{i} + \alpha_{ik} + \beta_{ik} + \varepsilon_{ik}, \quad b_{k} \sim N(0, \sigma_b^2), \quad \varepsilon_{ik} \sim N(0, \sigma^2) \]
## Linear mixed model fit by REML. t-tests use Satterthwaite's method [
## lmerModLmerTest]
## Formula: bloodVL_change ~ treatment + overall_adhere + overall_safety +
## period + (1 | ptid)
## Data: merged
##
## REML criterion at convergence: 4827.4
##
## Scaled residuals:
## Min 1Q Median 3Q Max
## -3.5936 -0.5795 0.0153 0.6127 3.0873
##
## Random effects:
## Groups Name Variance Std.Dev.
## ptid (Intercept) 23.09 4.805
## Residual 445.60 21.109
## Number of obs: 540, groups: ptid, 180
##
## Fixed effects:
## Estimate Std. Error df t value
## (Intercept) 73.4552 6.7058 419.7421 10.954
## treatmentGel B -6.7916 2.3555 417.1354 -2.883
## treatmentGel C -9.0880 2.2967 391.5595 -3.957
## overall_adhere 0.9365 0.1882 269.4894 4.975
## overall_safetyNo Adverse Event 26.4624 3.4675 521.9424 7.632
## periodperiod2 -2.3295 2.2271 356.0129 -1.046
## periodperiod3 -1.5433 2.2252 355.4545 -0.694
## Pr(>|t|)
## (Intercept) < 0.0000000000000002 ***
## treatmentGel B 0.00414 **
## treatmentGel C 0.000090106833739 ***
## overall_adhere 0.000001161748206 ***
## overall_safetyNo Adverse Event 0.000000000000111 ***
## periodperiod2 0.29629
## periodperiod3 0.48842
## ---
## Signif. codes: 0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
##
## Correlation of Fixed Effects:
## (Intr) trtmGB trtmGC ovrll_ ov_NAE prdpr2
## treatmntGlB -0.437
## treatmntGlC -0.359 0.538
## overall_dhr -0.832 0.328 0.247
## ovrll_sfNAE -0.616 0.080 0.032 0.196
## periodperd2 -0.129 -0.009 -0.006 -0.026 -0.038
## periodperd3 -0.173 0.001 0.001 0.004 0.009 0.499
| Comparison | Beta | 95% CI | p-value |
|---|---|---|---|
| Intercept (Pill A, Period 1, Sequence 0, No Adherence or AE) | 73.5 | 60.3, 86.6 | <0.001 |
| Treatment | <0.001 | ||
| Â Â Â Â Gel B vs Pill A | -6.8 | -11.4, -2.2 | |
| Â Â Â Â Gel C vs Pill A | -9.1 | -13.6, -4.6 | |
| Additional Day of Adherence | 0.9 | 0.6, 1.3 | <0.001 |
| Adverse Event | <0.001 | ||
| Â Â Â Â No Adverse Event | 26.5 | 19.7, 33.3 | |
| Period | 0.6 | ||
| Â Â Â Â Period 2 vs Period 1 | -2.3 | -6.7, 2.1 | |
| Â Â Â Â Period 3 vs Period 1 | -1.5 | -5.9, 2.8 | |
| Abbreviation: CI = Confidence Interval | |||
## contrast estimate SE df t.ratio p.value
## Pill A - Gel B 6.79 2.36 417 2.882 0.0115
## Pill A - Gel C 9.09 2.30 391 3.956 0.0003
## Gel B - Gel C 2.30 2.24 359 1.027 0.5602
##
## Results are averaged over the levels of: overall_safety, period
## Degrees-of-freedom method: kenward-roger
## P value adjustment: tukey method for comparing a family of 3 estimates
## contrast estimate SE df t.ratio p.value
## period1 - period2 2.330 2.23 355 1.046 0.5484
## period1 - period3 1.543 2.23 355 0.694 0.7674
## period2 - period3 -0.786 2.23 356 -0.353 0.9337
##
## Results are averaged over the levels of: treatment, overall_safety
## Degrees-of-freedom method: kenward-roger
## P value adjustment: tukey method for comparing a family of 3 estimates
Skin PK
Linear Model
##
## Call:
## lm(formula = skinVL_change ~ treatment + overall_adhere + overall_safety +
## period, data = merged)
##
## Residuals:
## Min 1Q Median 3Q Max
## -112.388 -22.128 1.035 20.921 115.662
##
## Coefficients:
## Estimate Std. Error t value Pr(>|t|)
## (Intercept) 105.6003 9.9680 10.594 < 0.0000000000000002
## treatmentGel B -24.4131 3.6314 -6.723 0.000000000046
## treatmentGel C -36.9951 3.5493 -10.423 < 0.0000000000000002
## overall_adhere 1.8154 0.2753 6.594 0.000000000103
## overall_safetyNo Adverse Event 55.7940 5.2166 10.696 < 0.0000000000000002
## periodperiod2 0.8567 3.4535 0.248 0.804
## periodperiod3 1.6225 3.4507 0.470 0.638
##
## (Intercept) ***
## treatmentGel B ***
## treatmentGel C ***
## overall_adhere ***
## overall_safetyNo Adverse Event ***
## periodperiod2
## periodperiod3
## ---
## Signif. codes: 0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
##
## Residual standard error: 32.74 on 533 degrees of freedom
## Multiple R-squared: 0.3581, Adjusted R-squared: 0.3508
## F-statistic: 49.55 on 6 and 533 DF, p-value: < 0.00000000000000022
| Comparison | Beta | 95% CI | p-value |
|---|---|---|---|
| Intercept (Pill A, Period 1, Sequence 0, No Adherence or AE) | 105.6 | 86.0, 125.2 | <0.001 |
| Treatment | <0.001 | ||
| Â Â Â Â Gel B vs Pill A | -24.4 | -31.5, -17.3 | |
| Â Â Â Â Gel C vs Pill A | -37.0 | -44.0, -30.0 | |
| Additional Day of Adherence | 1.8 | 1.3, 2.4 | <0.001 |
| Adverse Event | <0.001 | ||
| Â Â Â Â No Adverse Event | 55.8 | 45.5, 66.0 | |
| Period | 0.9 | ||
| Â Â Â Â Period 2 vs Period 1 | 0.9 | -5.9, 7.6 | |
| Â Â Â Â Period 3 vs Period 1 | 1.6 | -5.2, 8.4 | |
| Abbreviation: CI = Confidence Interval | |||
## contrast estimate SE df t.ratio p.value
## Pill A - Gel B 24.4 3.63 533 6.723 <.0001
## Pill A - Gel C 37.0 3.55 533 10.423 <.0001
## Gel B - Gel C 12.6 3.47 533 3.631 0.0009
##
## Results are averaged over the levels of: overall_safety, period
## P value adjustment: tukey method for comparing a family of 3 estimates
## contrast estimate SE df t.ratio p.value
## period1 - period2 -0.857 3.45 533 -0.248 0.9666
## period1 - period3 -1.623 3.45 533 -0.470 0.8853
## period2 - period3 -0.766 3.45 533 -0.222 0.9733
##
## Results are averaged over the levels of: treatment, overall_safety
## P value adjustment: tukey method for comparing a family of 3 estimates
Linear Mixed Model
## Linear mixed model fit by REML. t-tests use Satterthwaite's method [
## lmerModLmerTest]
## Formula: skinVL_change ~ treatment + overall_adhere + overall_safety +
## period + (1 | ptid)
## Data: merged
##
## REML criterion at convergence: 5269.4
##
## Scaled residuals:
## Min 1Q Median 3Q Max
## -3.4333 -0.6760 0.0316 0.6391 3.5333
##
## Random effects:
## Groups Name Variance Std.Dev.
## ptid (Intercept) 0 0.00
## Residual 1072 32.74
## Number of obs: 540, groups: ptid, 180
##
## Fixed effects:
## Estimate Std. Error df t value
## (Intercept) 105.6003 9.9680 533.0000 10.594
## treatmentGel B -24.4131 3.6314 533.0000 -6.723
## treatmentGel C -36.9951 3.5493 533.0000 -10.423
## overall_adhere 1.8154 0.2753 533.0000 6.594
## overall_safetyNo Adverse Event 55.7940 5.2166 533.0000 10.696
## periodperiod2 0.8567 3.4535 533.0000 0.248
## periodperiod3 1.6225 3.4507 533.0000 0.470
## Pr(>|t|)
## (Intercept) < 0.0000000000000002 ***
## treatmentGel B 0.000000000046 ***
## treatmentGel C < 0.0000000000000002 ***
## overall_adhere 0.000000000103 ***
## overall_safetyNo Adverse Event < 0.0000000000000002 ***
## periodperiod2 0.804
## periodperiod3 0.638
## ---
## Signif. codes: 0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
##
## Correlation of Fixed Effects:
## (Intr) trtmGB trtmGC ovrll_ ov_NAE prdpr2
## treatmntGlB -0.429
## treatmntGlC -0.354 0.534
## overall_dhr -0.826 0.311 0.234
## ovrll_sfNAE -0.627 0.079 0.033 0.206
## periodperd2 -0.137 -0.008 -0.005 -0.025 -0.037
## periodperd3 -0.180 0.001 0.001 0.004 0.009 0.499
## optimizer (nloptwrap) convergence code: 0 (OK)
## boundary (singular) fit: see help('isSingular')
| Comparison | Beta | 95% CI | p-value |
|---|---|---|---|
| Intercept (Pill A, Period 1, Sequence 0, No Adherence or AE) | 105.6 | 86.0, 125.2 | <0.001 |
| Treatment | <0.001 | ||
| Â Â Â Â Gel B vs Pill A | -24.4 | -31.5, -17.3 | |
| Â Â Â Â Gel C vs Pill A | -37.0 | -44.0, -30.0 | |
| Additional Day of Adherence | 1.8 | 1.3, 2.4 | <0.001 |
| Adverse Event | <0.001 | ||
| Â Â Â Â No Adverse Event | 55.8 | 45.5, 66.0 | |
| Period | 0.9 | ||
| Â Â Â Â Period 2 vs Period 1 | 0.9 | -5.9, 7.6 | |
| Â Â Â Â Period 3 vs Period 1 | 1.6 | -5.2, 8.4 | |
| Abbreviation: CI = Confidence Interval | |||
## contrast estimate SE df t.ratio p.value
## Pill A - Gel B 24.4 3.63 412 6.721 <.0001
## Pill A - Gel C 37.0 3.55 388 10.422 <.0001
## Gel B - Gel C 12.6 3.47 359 3.631 0.0009
##
## Results are averaged over the levels of: overall_safety, period
## Degrees-of-freedom method: kenward-roger
## P value adjustment: tukey method for comparing a family of 3 estimates
## contrast estimate SE df t.ratio p.value
## period1 - period2 -0.857 3.45 356 -0.248 0.9666
## period1 - period3 -1.623 3.45 355 -0.470 0.8853
## period2 - period3 -0.766 3.45 356 -0.222 0.9733
##
## Results are averaged over the levels of: treatment, overall_safety
## Degrees-of-freedom method: kenward-roger
## P value adjustment: tukey method for comparing a family of 3 estimates